chiral chlorothionate compounds and their use in separating a mixture of enantiomers or antipodes of an alcohol and / or in deoxygenating a mixture of enantiomers or antipodes of an alcohol

Abstract

The present invention relates to chiral chlorothionate compounds, derived from chiral binols, which are of great utility in the total synthesis of molecules of interest; their preparation process; their use for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol; a process for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol using such chiral chlorothionate compounds; the use of chiral chlorothionate compounds for the deoxygenation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol into a corresponding enantiopure alkane, in particular via the Barton-McCombie reaction; and a process for deoxygenating an alcohol in the form of a racemic or enantioenriched mixture. of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds. Figure to be published: no figure

Description

Title of the invention: Chiral chlorothionate compounds and their use for separating a mixture of enantiomers or antipodes of an alcohol and / or for deoxygenating a mixture of enantiomers or antipodes of an alcohol

[0001] The present invention relates to chiral chlorothionate compounds, derived from chiral binols, which are of great utility in the total synthesis of molecules of interest; their preparation process; their use for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol; a process for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol using such chiral chlorothionate compounds; the use of chiral chlorothionate compounds for the deoxygenation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol into corresponding enantiopure alkanes, in particular via the Barton-McCombie reaction; and a process for deoxygenating an alcohol in the form of a racemic or enantioenriched with enantiomers or antipodes, to form alkanes in the form of enantiopure compounds.

[0002] The multi-step synthesis of chiral molecules of interest very often requires obtaining strictly enantiopure molecules, and in particular the use of enantiopure alcohols.

[0003] To obtain enantiopure alcohols, it is known to use liquid chromatography having a chiral stationary phase. Another solution consists of esterifying an alcohol in the form of a racemic mixture with a chiral carboxylic acid, such as (S)-(+)-2-methoxy-2-(l-naphthyl)propionic acid (MaNP acid), to form a diastereomeric mixture of activated esters which are then separated by conventional silica gel liquid chromatography or reversed-phase liquid chromatography.

[0004] Other chiral carboxylic acids have been described in Harada, Molecules, 2016, 21, 1328, 1-37 and are listed below with MaNP acid:

[0005] [Chem.l] MATsj-I CT? "do ÇS 11F

[0006] In general, it is quite difficult to separate enantiomers or diastereomers composed of carbon, hydrogen, and oxygen atoms by chromatography, particularly when they include aliphatic chains. Furthermore, as reported by Harada, depending on the racemic alcohol used, chromatographic separation of diastereomers is not always efficient. Consequently, there is a need for new chiral compounds capable of separating racemic mixtures of alcohols.

[0007] Furthermore, when it is necessary to synthesize an enantiopure alkane from a racemic alcohol in a multi-step synthesis, the aforementioned separation of diastereomers must be followed by a deprotection step to form the enantiopure alcohol, which is then reduced to the enantiopure alkane as shown by Harada in the synthesis scheme below:

[0008] [Chem.2]

[0009] This can represent a large number of steps, particularly when the alcohol includes one or more groups sensitive to the conditions of alcohol reduction to alkane, making it necessary to protect such groups beforehand.

[0010] There is therefore a need for new chiral compounds allowing both the splitting of enantiomers and the transformation of an alcohol into an alkane to form enantiopure alkanes from a racemic mixture of alcohols.

[0011] The invention has as its first object a chiral chlorothionate compound, derived from a chiral binol, characterized in that it corresponds to the following formula (I) or (!'):

[0012] [Chem.3] in which: * R1 is an alkyl group or an aryl group, * R2 is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or a carbonyl group -C(=O)-R3, in which R3 is a heteroalkyl, alkyl, or aryl group.

[0013] Thanks to this chiral chlorothionate compound, it is possible to carry out multi-step syntheses involving both racemic or enantioenriched alcohols that one wishes to separate and a deoxygenation reaction to obtain the corresponding enantiopure alkanes.

[0014] A binol is also called l,l'-bi-2-naphthol. It is a derivative of a naphthalene dimer exhibiting axial chirality of the atropoisomeric type, that is to say that the rotation around the single naphthyl-naphtyl bond is blocked due to the steric hindrance of the hydroxyl groups in the ortho position with respect to this bond.

[0015] Chlorothionate compounds (I) and (I') are chiral compounds, and more particularly atropoisomers. Compound (I) is a derivative of (R)-binol and compound (I') is a derivative of (Sj-binol.

[0016] The chlorothionate (I) or (I') compound is a binaphtyl chiral skeleton that can be substituted by an R2 group in the ortho position of naphthols. It has proven particularly useful, on the one hand, for forming activated compounds of the type Thiocarbonates are easily separable and readily reducible to alkanes. This allows, in a total synthesis of molecules of interest, the transformation of alcohols into a racemic mixture or an enantiomerically enriched enantiopure alkanes.

[0017] The present invention provides a practical and simple solution for separating enantiomers during a multi-step sequence including a Barton-McCombie reaction on a racemic or enantioenriched intermediate having an alcohol function (for example, splitting of enantiomers in the case of a Barton-McCombie reaction).

[0018] General definitions

[0019] According to the invention, the term "alkyl" refers to saturated, linear or branched, hydrocarbon aliphatic groups comprising, unless otherwise specified, from 1 to 20 carbon atoms, and preferably from 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl groups.

[0020] According to the invention, the term "heteroalkyl" refers to saturated, linear or branched, hydrocarbon aliphatic groups comprising, unless otherwise specified, from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms; and comprising at least one heteroatom such as an oxygen atom or a nitrogen atom. Examples include alkoxy groups or amine groups.

[0021] According to the invention, the term "cycloalkyl" refers to saturated cyclic or polycyclic aliphatic hydrocarbon groups comprising, unless otherwise specified, from 3 to 30 carbon atoms, and preferably from 5 to 20 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0022] According to the invention, the term "heterocycloalkyl" refers to saturated cyclic or polycyclic aliphatic hydrocarbon groups comprising, unless otherwise specified, from 3 to 30 carbon atoms, preferably from 5 to 20 carbon atoms; and comprising at least one heteroatom such as an oxygen atom or a nitrogen atom. Examples include tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, etc.

[0023] According to the invention, the term "aryl" refers to cyclic or polycyclic aromatic groups comprising, unless otherwise specified, from 5 to 20 carbon atoms. Examples of aryl groups include phenyl and naphthyl groups.

[0024] According to the invention, the term "heteroaryl" refers to cyclic or polycyclic aromatic groups comprising, unless otherwise specified, from 5 to 20 atoms, and comprising at least one heteroatom such as an oxygen atom, a sulfur atom, or a nitrogen atom. Examples include pyrrolyl, pyrazolyl, 1,2,3- groups. triazolyl, 1,2,4-triazolyl, tetrazolyl, and 1,2,3-triazinyl imidazolyl, thiazolyl, oxazolyl, furanyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzothazolyl, quinolinyl, isoquinolinyl.

[0025] The "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl" groups can be substituted by one or more substituents. Among these substituents, the following may be mentioned: amino, hydroxy, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy, or carboxyalkyl groups.

[0026] Definition of R1

[0027] The alkyl group can be a linear or branched alkyl group.

[0028] The alkyl group as group R1 is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl group.

[0029] The aryl group as group R1 can be a cyclic or polycyclic aromatic group.

[0030] The aryl group as group R1 is preferably an aryl group comprising from 5 to 12 carbon atoms, particularly preferably from 5 to 10 carbon atoms, more particularly preferred is a phenyl, naphthyl or anthracenyl group, and even more particularly preferred is a phenyl group.

[0031] Substituted aryl group

[0032] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom.

[0033] A phenyl group substituted at ortho or meta position(s) is preferred.

[0034] The alkyl group as a substituent of the aryl group can be an alkyl group linear or branched.

[0035] The alkyl group as a substituent of the aryl group can comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0036] The halogen atom as a substituent of the aryl group can preferably be a fluorine atom.

[0037] According to a preferred embodiment of the invention, the aryl group as group R1 is a phenyl group or a phenyl group substituted at ortho or meta position(s) by a substituent as defined above.

[0038] In a particularly preferred embodiment, the R1 group is an alkyl group.

[0039] Definition of R2

[0040] The halogen atom is preferably a fluorine, iodine, bromine or chlorine atom, and particularly preferably a fluorine atom.

[0041] The alkyl group can be a linear or branched alkyl group.

[0042] The alkyl group as group R2 is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl, ethyl, or isopropyl group.

[0043] The aryl group as group R2 is preferably an aryl group comprising from 5 to 12 carbon atoms, particularly preferably from 5 to 10 carbon atoms, and most particularly preferably is a phenyl group.

[0044] Substituted aryl group

[0045] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom, and preferably by a halogen atom.

[0046] A phenyl group substituted at ortho or meta position(s) is preferred.

[0047] The alkyl group as a substituent of the aryl group can be an alkyl group linear or branched.

[0048] The alkyl group as a substituent of the aryl group can comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0049] The halogen atom as a substituent of the aryl group can be an iodine, chlorine, fluorine, or bromine atom, and preferably a fluorine atom.

[0050] According to a preferred embodiment of the invention, the aryl group as group R2 is a phenyl group or a phenyl group substituted at ortho or meta position(s) by a substituent as defined above.

[0051] In the carbonyl group -C(=O)-R3 as group R2, group R3 is a heteroalkyl, alkyl or aryl group.

[0052] The alkyl group can be a linear or branched alkyl group.

[0053] The alkyl group as group R3 is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl group.

[0054] The heteroalkyl group can be a linear or branched heteroalkyl group.

[0055] The heteroalkyl group as group R3 is preferably a heteroalkyl group comprising from 1 to 10 carbon atoms and at least one heteroatom selected from an oxygen atom and a nitrogen atom, particularly preferably comprising from 1 to 5 carbon atoms and at least one heteroatom selected between an oxygen atom and a nitrogen atom, and particularly preferred is a methoxy group.

[0056] The aryl group as group R3 is preferably an aryl group comprising from 5 to 12 carbon atoms, particularly preferably from 5 to 10 carbon atoms, more particularly preferably is a phenyl group.

[0057] Substituted aryl group

[0058] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom.

[0059] A phenyl group substituted at ortho or meta position(s) is preferred.

[0060] The alkyl group as a substituent of the aryl group can be an alkyl group linear or branched.

[0061] The alkyl group as a substituent of the aryl group may comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0062] The halogen atom as a substituent of the aryl group may preferably be a fluorine atom.

[0063] According to a preferred embodiment of the invention, the aryl group as group R3 is a phenyl group or a phenyl group substituted at ortho or meta position(s) by a substituent as defined above.

[0064] In a particularly preferred embodiment, the R3 group is a heteroalkyl group.

[0065] In a particularly preferred embodiment, the R2 group is a hydrogen atom or an alkyl group.

[0066] According to a more particularly preferred embodiment of the invention, the chiral chlorothionate compound (I) (respectively (!')) is such that: * R1 is an alkyl group, and * R2 is a hydrogen atom or an alkyl group.

[0067] More specifically, the chiral chlorothionate compound of the invention (I) or (!') is chosen from the following compounds:

[0068] [Chem.4] 0-0 0-2}

[0069] The invention has as its second object a process for preparing a chlorothionate compound (I) or (II') according to the first object of the invention, characterized in that it comprises at least one step (i) of reacting a chiral substituted alcohol, derived from a chiral binol, in the presence of thiophosgene and a strong base, said chiral substituted alcohol corresponding to the following formula (II) or (II'):

[0070] [Chem.5] in which R1 and R2 are as defined in the first object of the invention.

[0071] The strong base can be chosen from NaH, KH, or LiHMDS.

[0072] Step i) can be carried out in a polar aprotic solvent, preferably chosen from tetrahydrofuran or diethyl ether.

[0073] Step i) is preferably carried out at room temperature (e.g. about 18-25°C).

[0074] Step i) is preferably carried out with a slight excess of strong base, e.g. 1.1-1.2 equivalents relative to the chiral substituted alcohol.

[0075] Step i) is preferably carried out with an excess of thiophosgene, e.g. 2-4 equivalents relative to the chiral substituted alcohol.

[0076] The chiral substituted alcohol corresponding to formula (II) or (II') can be obtained beforehand in one or more steps, depending on the nature of the R1 and R2 groups chosen. In particular, when R2 is a hydrogen atom, the process may further include a step i0) in which one of the hydroxyl groups of (R)-binol or (^-binol) is protected by an R1 group as defined in the invention. When R2 is not a hydrogen atom, the process may further include a step i01) in which the ortho positions of (R)-binol or (S)-binol are substituted by an R2 group as defined in the invention, and then one of the hydroxyl functions of the (R)-binol or (^-binol) substituted at ortho positions is protected by an R1 group as defined in the invention in a step i02.

[0077] Step i0) or i02) can be carried out in the presence of an alkyl halide R'-X, in which R1 is an alkyl group as defined in the invention, and X is a halogen atom such as an iodine atom; and a base such as K2CO3, preferably by heating to a temperature of 40 to 100°C (e.g., about 60°C).

[0078] When R1 is a phenyl group, step iO) or iO2) can be carried out by using a hypervaient iodine-based reagent after mono-deprotonation of the phenol with a strong base, followed by a coupling reaction mediated by iodonium-type reagents.

[0079] The step iOl) can be carried out in several steps, including the protection of the hydroxyl functions of the (R)-binol or the (^-binol then the substitution of the ortho positions by an R2 group as defined in the invention but different from a hydrogen atom, then the deprotection of the hydroxyl functions.

[0080] The protecting group of the hydroxyl functions of (R)-binol or (^-binol) can be an alkoxyalkyl ether such as methoxymethyl ether.

[0081] The protection of the hydroxyl functions by the alkoxyalkyl ether is obtained by the reaction of the phenolate in the presence of a halogenodialkyl ether, preferably a chlorodialkyl ether such as chloromethyl ether.

[0082] The substitution of ortho positions by an R2 group can be carried out in the presence of an R2-X alkyl halide, in which R2 is an alkyl group as defined in the invention, and X is a halogen atom such as an iodine atom; and a strong base such as BuLi.

[0083] The installation of a carbonyl group as the R2 group can be carried out in the same way, namely by the formation of an organolithium from the bis-protected phenol, preferably in the form of methoxymethyl ether, followed by its trapping by a bis-alkyl carbonate or by a chloroalkyl carbonate (in order to form the esters), or by its trapping by an aliphatic or aromatic aldehyde followed by oxidation of the transient alcohol to access the corresponding ketones.

[0084] The invention has as its third object the use of a chiral chlorothionate compound (I) or (!') according to the first object of the invention, for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol.

[0085] The chiral chlorothionate compound (I) or (!') according to the first object of the invention is particularly useful for the separation of a racemic mixture of an alcohol. The chiral chlorothionate compound (I) or (!') according to the first object of the invention thus makes it possible to separate two enantiomers or two antipodes of a racemic or enantioenriched mixture of an alcohol, or in other words, to carry out a resolution.

[0086] In the invention, the term "racemic or enantiomerically enriched mixture of an alcohol" means a compound having an alcohol group in the form of two enantiomers, the relative proportion of each enantiomer being variable, for example, 50% by mole of one enantiomer and 50% by mole of the other enantiomer for a racemic mixture, and x% by mole of one enantiomer and y% by mole of the other enantiomer, with 0% < x < 100% and 0% < y < 100%. The alcohol in the form of two enantiomers comprises at least one asymmetric carbon atom (denoted -C*). The alcohol may comprise other asymmetric carbons so as to form a racemic or enantiomerically enriched mixture of two antipodes. The asymmetric carbon atom is not necessarily bonded to the alcohol group.

[0087] An asymmetric carbon or center is also referred to in the invention as a chiral or stereogenic carbon or center.

[0088] Alcohol can be a primary, secondary, or tertiary alcohol, and preferably a secondary alcohol. Alcohol is preferably an aliphatic alcohol.

[0089] The alcohol may be an alcohol of formula (III) as defined below in the fourth object of the invention.

[0090] The R2 group on the compound of formula (I) or (!') allows the separation coefficient of the diastereomers formed by coupling to be modulated and the separation of the racemic mixture of said alcohol to be optimized.

[0091] The invention has as its fourth object a method for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol, characterized in that it comprises at least the following steps: a) the coupling of an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (!') according to the first object of the invention, to form two corresponding thiocarbonate diastereomers, and b) the separation of the two corresponding thiocarbonate diastereomers.

[0092] Coupling a) can be carried out under buffered or thermodynamic conditions, in the presence of a weak basis, or under kinetic conditions, in the presence of a strong basis.

[0093] The thermodynamic conditions are particularly suitable in the case of an alcohol that is not too crowded.

[0094] The kinetic conditions are particularly suitable in the case of a hindered alcohol.

[0095] The base is generally used in excess (e.g. 5 equivalents relative to the alcohol).

[0096] The weak base can be chosen from pyridine, 2,6-di-tert-butylpyridine, and 2,6-dimethylpyridine.

[0097] Under thermodynamic conditions, step a) is preferably carried out in an aprotic, polar or nonpolar solvent, such as dichloromethane, dimethylformamide, or acetonitrile.

[0098] The strong base can be LiHMDS or KHMDS.

[0099] Under kinetic conditions, step a) is preferably carried out in a polar aprotic solvent such as tetrahydrofuran or diethyl ether.

[0100] Step a) preferably uses an excess of chiral chlorothionate compound (I) or (!') relative to alcohol, and particularly preferably from 1.5 to 3.5 equivalents relative to alcohol (e.g. 2 equivalents).

[0101] The two thiocarbonates obtained at the end of step a) are easily separable according to step b).

[0102] Step b) is carried out according to conventional methods, in particular by liquid chromatography, possibly under high pressure, and preferably by silica gel chromatography.

[0103] Alcohol can be a primary, secondary, or tertiary alcohol, and preferably a secondary alcohol. Alcohol is preferably an aliphatic alcohol.

[0104] The alcohol may in particular be denoted R*-OH, with the asterisk representing at least one stereogenic or chiral center within the alcohol R*-OH.

[0105] The thiocarbonates obtained at the end of step b) are novel in themselves and in this case can correspond to the following formula (IV) or (IV'):

[0106] [Chem.6] in which R1 and R2 are as defined in the first object of the invention and the group R is a remnant of a primary, secondary or tertiary alcohol selected from molecules of interest, such as, for example, molecules with therapeutic aims, the asterisk denoting at least one stereogenic center within the group R.

[0107] When the chiral chlorothionate (I) according to the first object of the invention is used in the process according to the fourth object of the invention, a thiocarbonate compound of formula (IV) is obtained at the end of step a) in the form of a mixture of two diastereomers. When the chiral chlorothionate (I') according to the first object of the invention is used in the process according to the fourth object of the invention, a thiocarbonate compound of formula (IV') is obtained at the end of step a) in the form of a mixture of two diastereomers. Then, at the end of step b), the diastereomers are separated.

[0108] These thiocarbonates of formula (IV) or (IV') have the advantage of being able to be easily deoxygenated, in particular via the Barton-McCombie reaction.

[0109] The process preferably uses in step a) an alcohol corresponding to the following formula (III):

[0110] [Chem.7] in which: - compound (III) is in the form of a racemic or enantio-enriched mixture of enantiomers or antipodes, - R4 is chosen from an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, or a polycyclic aryl group, or together form a cycloalkylene group or a heterocycloalkylene group, and - R5 and R6, identical or different, are chosen, independently of each other, from a hydrogen atom, an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, or a polycyclic aryl group, - said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylene, heterocycloalkylene, polycyclic aryl group, being able to be substituted by one or more substituents chosen from an alkyl group, a cyano group (CN), a carboxylic acid group (COOH), an alkyl ester group, a phosphonic acid group (PO(OH)2), an alkyl ester group of phosphonic acid, a sulfonic acid group (SO3H), an alkyl ester group of sulfonic acid, a dialkyl or monoalkyl amide group.

[0111] The alcohol is preferably a primary or secondary alcohol (i.e. at least one of the groups R5 or R6 is a hydrogen atom), and preferably still a secondary alcohol (R5 is a hydrogen atom and R6 is not a hydrogen atom or vice versa).

[0112] In a particular embodiment, the alcohol is chosen from menthol and any other primary or secondary complex alcohol present in the form of two antipodes.

[0113] According to this embodiment using alcohol (III), the thiocarbonate obtained at the end of step b) corresponds to any one of the following formulas (IVa), (IVb), (IVa'), (IVb'):

[0114] [Chem.8] (IVa" J (FW) in which R1, R2, R4, R5, and R6 are as defined in the invention, and the asterisk denotes at least one stereogenic center within the group -CR4R5R6.

[0115] Thiocarbonates (IVa) and (IVb) [respectively thiocarbonates (IVa') and (IVb')] are distinguished from each other by the inverted configuration of one or all of the stereogenic centers within the -CR4R5R6 group. In other words, for a thiocarbonate (IVa) [respectively a thiocarbonate (IVa')] having a stereogenic center of configuration (S) within the -CR4R5R6 group, the thiocarbonate (IVb) [respectively thiocarbonate (IVb')] then generated a center of the configuration group (S) -CR4R5R6; for a thiocarbonate (IVa) [respectively a thiocarbonate (IVa')] having several stereogenic centers of configurations (1S, 2R, 3S) within the -CR4R5R6 group, the thiocarbonate (IVb) [respectively thiocarbonate (IVb')] then has several configurations. (IR, 2S, 3R) within the -CR4R5R6 group.

[0116] When the chiral chlorothionate (I) according to the first object of the invention is used in the process according to the fourth object of the invention, two diastereomers of formulas (IVa) and (IVb) are obtained at the end of step a) and are separated according to step b). When the chiral chlorothionate (I') according to the first object of the invention is used in the process according to the fourth object of the invention, two diastereomers of formulas (IVa') and (IVb') are obtained at the end of step a) and are separated according to step b).

[0117] The two thiocarbonates (IVa) and (IVb) obtained at the end of step a) [respectively the two thiocarbonates (IVa') and (IVb') obtained at the end of step a)] are easily separable according to step b).

[0118] The process may further include a step c) of deprotection of at least one of the diastereomers recovered in step b) to form said alcohol (e.g. said alcohol (III)), in an enantiopure form (i.e. a single enantiomer or a single antipode).

[0119] Deprotection c) can be carried out by saponification, in particular using an alcohol such as methanol or ethanol as a solvent, and a weak base, for example chosen from carbonates and hydrogen carbonates. The use of a stronger base such as sodium methoxide or sodium ethoxide may also be considered.

[0120] When the alcohol carries the stereogenic center (i.e., the carbon of the hydroxyl function is a stereogenic center), step c) can lead to one of the following enantiopure alcohols:

[0121] [Chem.9] (IlLa) (IlLb) with R4, R5, and R6 being as defined in the invention, and the asterisk denotes the stereogenic center.

[0122] The thiocarbonates corresponding to the formulas (IVa), (IVb), (IVa') and (IVb'), obtained at the end of step b) have the advantage of being able to be easily deoxygenated, in particular via the Barton-McCombie reaction, once the separation of the two diastereomers has been carried out while preserving their stereochemistry.

[0123] Thus, the invention has as its fifth object the use of a chiral chlorothionate compound (I) or (I') according to the first object of the invention, for the deoxygenation of an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes in corresponding enantiopure alkanes, in particular via the Barton-McCombie reaction.

[0124] In particular, the alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes is deoxygenated to a corresponding enantiopure alkane, via the formation of a key thiocarbonate intermediate as defined in the invention which is in the form of two diastereomers which are on the one hand easily separable and on the other hand easily reduced after separation.

[0125] Alcohol or alcohol (III) may be a primary, secondary or tertiary alcohol and preferably a primary or secondary alcohol.

[0126] The alcohol is preferably an alcohol of formula (III) as defined in the invention, and even more preferably in which: - alcohol (III) is a primary alcohol (i.e. R5 = R6 = one hydrogen atom) and at least one asymmetric carbon is carried by the R4 group; - Alcohol (III) is a secondary alcohol (i.e., R5 = a hydrogen atom) and at least one asymmetric carbon is attached to R4, R5, or the carbon bearing the hydroxyl group; or - alcohol (III) is a tertiary alcohol (i.e. R5 and R6 are each different by one hydrogen atom), R5 and R6 are identical and R4 includes at least one asymmetric carbon.

[0127] One of the two thiocarbonates of formula (IV) or one of the two thiocarbonates of formula (IV'), and in particular one of the thiocarbonates of formula (IVa), (IVb), (IVa'), or (IVb'), obtained from the chlorothionate compound (I) or (I') according to the first object of the invention, can be deoxygenated while retaining the initial stereochemistry by: - radical reaction on the thiocarbonate function in the presence of a hydride donor such as Bu3SnH and a radical initiator such as AIBN, or - by any alternative method to the Barton-McCombie method such as those involving silane hydrides.

[0128] The so-called "Barton-McCombie" reaction is a transformation very frequently used in multi-step synthesis, particularly in syntheses aimed at producing complex molecules. To date, only achial reagents have been used in such a reaction. The chlorothionate compounds (I) and (I') of the invention are stable and allow for the efficient deoxygenation of aliphatic alcohols.

[0129] The invention relates as a sixth object a process for deoxygenating an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds, characterized in that it comprises at least the following steps: a) the coupling of an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (I') conforming to the first object of the invention, to form two corresponding thiocarbonate diastereomers, b) the separation of the two corresponding thiocarbonate diastereomers, and d) the reduction of at least one of the two thiocarbonate diastereomers in the presence of a hydride donor.

[0130] The alcohol may be an alcohol of formula (III) as defined in the invention.

[0131] The alcohol is preferably an alcohol of formula (III) in which: - alcohol (III) is a primary alcohol (i.e. R5 = R6 = one hydrogen atom) and at least one asymmetric carbon is carried by the R4 group; - Alcohol (III) is a secondary alcohol (i.e., R5 = a hydrogen atom) and at least one asymmetric carbon is attached to R4, R5, or the carbon bearing the hydroxyl group; or - alcohol (III) is a tertiary alcohol (i.e. R5 and R6 are each different by one hydrogen atom), R5 and R6 are identical and R4 includes at least one asymmetric carbon.

[0132] Step d) is preferably a radical reaction on the thiocarbonate function in the presence of a hydride donor such as Bu3SnH and a radical initiator such as AIBN, or any alternative method to the Barton-McCombie such as those involving silane hydrides.

[0133] Chlorothionates (I) or (I') thus have a dual purpose: they allow the separation of racemic alcohols by simple purification on silica gel, but also the deoxygenation of these alcohols during the subsequent step of reduction under radical conditions.

[0134] The invention thus makes it possible to anticipate the asymmetric synthesis of molecules of interest more effectively through strategies based on a Barton-McCombie deduplication step. This can be of particular relevance in the field of the synthesis of complex bioactive molecules; a field that often employs Barton-McCombie reactions and requires the production of strictly enantiopure molecules.

[0135] The present invention is illustrated by the following embodiments, to which it is not, however, limited. Examples

[0136] All reactions were carried out under an argon atmosphere using dry solvents under anhydrous conditions, and all reagents were purchased from commercial suppliers without further purification. Unless otherwise specified, the reactions were carried out at room temperature (i.e., at a temperature ranging from 18 to 25°C and preferably at a temperature of about 21°C). Anhydrous dichloromethane (CH₂C₁₂, DCM) and tetrahydrofuran (THF) were obtained by filtering commercially available, oxygen-free, pre-dried formulations through activated alumina columns. Anhydrous methanol (MeOH) was purchased in the best commercial grade and used without further purification. Ethyl acetate (EtOAc), dichloromethane, diethyl ether (Et₂O), pentane, methanol (MeOH), cyclohexane, and petroleum ether (PET) were commercially available and used without anhydrous treatment. Unless otherwise stated, yields refer to chromatographically and spectroscopically homogeneous (¹H NMR) materials. Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm Merck silica gel plates (reference 60F-254).An ethanolic solution of phosphomolybdic acid or an aqueous solution of potassium permanganate and sodium hydroxide were used as developing agents. Merck silica gel (reference "60", particle size: 40-63 µm) was used for column chromatography.

[0137] The nuclear magnetic resonance (NMR) spectra were recorded using a Bruker DPX-300, Bruker Avance I 300 MHz, or Bruker Avance II 400 MHz reference instrument and calibrated using a non-deuterated residual solvent as an internal reference (7.26 ppm and 77.16 ppm for *H and 13C NMR in CDC13, respectively). The following abbreviations were used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broadband signal.

[0138] IR (infrared) spectra were recorded between 4000 and 550 cm1 on a reference spectrometer “FT-IR Bruker IFS55 (OPUS / IR 3.0.2)”.

[0139] Optical rotation values ​​([a]25D) were recorded on a Jasco P2000 reference digital polarimeter at 25°C using a thermostable optical glass cell (path length of 100 mm).

[0140] The melting points (pf) were recorded on a “Buchi B-540” digital reference device.

[0141] High-resolution mass spectrometry (HRMS) analyses using electron fogging ionization (ESI) were obtained from the Centre for Structural Study and Analysis of Organic Molecules (CESAMO) of the Institute of Molecular Sciences (ISM, CNRS-UMR 5255, Talence, France).

[0142] Example 1: preparation of a binol chlorothionate according to the invention

[0143] A first binol(I-1) chlorothionate was prepared according to synthetic scheme 1 following :

[0144] [Chem. 10] (IM) DIAGRAM 1

[0145] Compound (II-1): Potassium carbonate (1.16 g, 8.38 mmol) was added at room temperature to a solution of compound 1, which is (7?)-BINOL (2 g, 6.98 mmols) in acetone (70 mL). After stirring for 1 h at this temperature, iodomethane (0.435 mL, 6.99 mmols) was added. The resulting mixture was stirred at 60°C for 16 h, then a saturated aqueous solution of NH4Cl (100 mL) was added at room temperature, and the mixture was diluted with EtOAc (140 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 30 mL). The organic phases were combined, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc / DCM / PET - 4 / 16 / 80) to obtain the chiral (II-1) substituted alcohol (1.92 g, 92% yield) as a white solid.

[0146] Rf = 0.22 (EtOAc / DCM / PET - 4 / 16 / 80)

[0147] 1 H NMR (300 MHz, CDC13) ô 8,08 (d, J = 9, Hz, 1H), 8,01 - 7,86 (m, 3H), 7,50 (d, 7=9,1 Hz, 1H), 7,45 - 7,22 (m, 6H), 7,12 (dd, J = 8,4, 1,3 Hz, 1H), 5,01 (s, 1H), 3,83 (s, 3H).

[0148] 13 C NMR (75 MHz, CDC13) ô 156,09, 151,35, 134,15, 133,87, 131,12, 129,90, 129,51, 129,24, 128,25 (2C), 127,43, 126,51, 125,02, 124,92, 124,27, 123,34, 117,59, 115,46, 115,11, 113,89, 56,74.

[0149] Compound (I-1): Sodium hydride (131 mg, 3.27 mmols) was added at room temperature to a solution of chiral substituted alcohol (II-1) (892 mg, 2.97 mmols) in anhydrous THF (30 mL). After stirring for 15 minutes at this temperature, the reaction mixture was added dropwise to a solution of thiophosgene (0.683 mL, 8.91 mmols) in anhydrous THF (30 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 h before being concentrated under reduced pressure. The crude product was purified by column chromatography. silica gel (eluent with Et2O / PET - 2 / 8) to obtain the compound chlorthionate (I -1 ) (819 mg, yield of 73%) in the form of a yellow solid.

[0150] pf = 139-141°C

[0151] Rf = 0.71 (Et2O / DCM / PET -3:7)

[0152] 1 H NMR (300 MHz, CDC13) ô 8.07 (dd, J = 9.0, 1.7 Hz, 2H), 7.96 (dd, J = 28.0, 8.1 Hz, 2H), 7.59 - 7.46 (m, 3H), 7.42 - 7.32 (m, 3H), 7.26 (ddd, J= 8.2, 6.7, 1.4 Hz, 1H), 7.15 (d, J= 8.6 Hz, 1H), 3.84 (s, 3H).

[0153] 13 C NMR (76 MHz, CDC13) ô 184.65, 155.10, 150.69, 133.84, 133.52, 132.38, 130.78, 129.60, 129.03, 128.38, 128.09, 127.05, 126.78, 126.70, 126.45, 125.54, 125.40, 123.80, 120.60, 116.03, 113.34, 56.53.

[0154] HRMS (ESI) exact mass calculated for C22Hi5O2C1KS+: m / z 417.01129 ([M + K]+), found: m / z^ 17.01177 ([M + K]+).

[0155] IR(film) vmax: 3059, 3005, 2936, 2839, 1622, 1592, 1509, 1462, 1268, 1245, 1205, 1185, 1148, 1085, 1031, 1014, 810, 750 cm1.

[0156] Example 2: preparation of a binol chlorothionate according to the invention

[0157] A second binol(I-2) chlorothionate was prepared according to the following synthetic scheme 2:

[0158] [Chem. 11]

[0159] Compound 2: To a solution of compound 1, which is (7?)-BINOL (3 g, 10.48 mmols) in anhydrous THF (105 mL), sodium hydride (628.7 mg, 26.20 mmols) was added at 0°C. After stirring for 15 minutes at room temperature, chloromethoxymethane (2.0 mL, 26.20 mmols) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then a saturated aqueous solution of NH4Cl (75 mL) was added, and the mixture was diluted with EtOAc (200 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 30 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: EtOAc / DCM / PET - 4 / 16 / 80) to obtain compound 2 (3.73 g, yield of 95%) in the form of a white solid.

[0160] Rf = 0.48 (EtO Ac / CH2C12 / PET - 6 / 24 / 70)

[0161] 1 H NMR (300 MHz, CDC13) ô 8,04 - 7,97 (m, 1H), 7,92 (dt, J= 8,4, 1,1 Hz, 1H), 7,64 (d, J = 9,0 Hz, 1H), 7,40 (ddd, J = 8,2, 6,4, 1,7 Hz, 1H), 7,31 - 7,21 (m, 2H), 3,20 (s, 3H).

[0162] 13 c NMR (76 MHz, CDC13) ô 152,76 (2C), 134,13 (2C), 129,99 (2C), 129,50 (2C), 127,98 (2C), 126,40 (2C), 125,66 (2C), 124,17 (2C), 121,40 (2C), 117,38 (2C), 95,29 (2C), 55,91 (2C).

[0163] Compound 3: To a solution of compound 2 (749 mg, 2.00 mmols) in anhydrous THF (50 mL), n-Butyllithium (5.2 mL, 1.17 M in hexanes) was added at 0°C for 5 minutes. After stirring for 2 hours at room temperature, iodomethane (0.374 mL, 6 mmols) was added at 0°C. The resulting mixture was stirred at this temperature for 15 minutes, then a solution of NH4Cl and water (volume ratio: 1 / 1, 30 mL) was added and the mixture was diluted with Et2O (100 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (2 x 15 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / PET - 3 / 97) to obtain compound 3 (780 mg, yield of 97%) in the form of a white solid.

[0164] Rf = 0.40 (Et2O / PET - 1 / 9)

[0165] 1 H NMR (300 MHz, CDC13) ô 7,96 - 7,83 (m, 4H), 7,43 (ddd, J= 8,1, 6,4, 1,6 Hz, 2H), 7,36 - 7,23 (m, 4H), 4,73 (d, J = 5,8 Hz, 2H), 4,62 (d, J = 5,8 Hz, 2H), 2,95 (s, 6H), 2,70 (d, J = 1,0 Hz, 6H).

[0166] 13 C NMR (75 MHz, CDC13) ô 153,24 (2C), 133,01 (2C), 131,59 (2C), 130,92 (2C), 129,75 (2C), 127,10 (2C), 126,12 (2C), 125,54 (2C), 125,35 (2C), 124,85 (2C), 98,63 (2C), 56,38 (2C), 17,85 (2C).

[0167] Compound 4: Concentrated hydrochloric acid (HCl) (4.12 mL, 135.7 mmol) was added dropwise at room temperature to a solution of compound 3 (780 mg, 1.938 mmol) in MeOH (40 mL). The resulting mixture was stirred at this temperature for 2 hours before being concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: EtOAc / Cyclohexane - 5 / 95) to obtain compound 4 (524 mg, 86% yield) as a slightly yellow solid.

[0168] Rf = 0.38 (Et2O / Pentane - 5 / 95)

[0169] 1 H NMR (300 MHz, CDC13) ô 7.93 - 7.79 (m, 4H), 7.38 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 7.28 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.14 (dq, J = 7.6, 0.8 Hz, 2H), 5.16 (s, 2H), 2.56 (d, J = 1.0 Hz, 6H).

[0170] 13 C NMR (75 MHz, CDC13) ô 152.19 (2C), 132.30 (2C), 130.86 (2C), 129.57 (2C), 127,69 (2C), 127,15 (2C), 126,52 (2C), 124,19 (2C), 124,05 (2C), 110,61 (2C), 17,13 (2C).

[0171] Compound (II-2): Potassium carbonate (1.42 g, 10.30 mmol) was added to a solution of compound 4 (2.70 g, 8.58 mmol) in acetone (86 mL) at room temperature. After stirring for 1 h at this temperature, iodomethane (0.534 mL, 8.58 mmol) was added. The resulting mixture was stirred at 60°C for 16 h, then a saturated aqueous solution of NH4Cl (120 mL) was added at room temperature, and the mixture was diluted with EtOAc (180 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / Pentane - 5 / 100) to obtain the chiral substituted alcohol (II-2) (2.38 g, yield of 85%) in the form of a white solid.

[0172] Rf = 0.47 (Et2O / Pentane - 5 / 95)

[0173] 1 H NMR (300 MHz, CDC13) ô 7.92 - 7.78 (m, 4H), 7.44 (ddd, J = 8.1, 6.6, 1.4 Hz, 1H), 7.33 (ddt, J = 8.1, 6.8, 1.3 Hz, 1H), 7.28-7.17 (m, 3H), 7.09 (ddt, J = 8.3, 1.4, 0.7 Hz, 1H), 5.14 (d, J = 0.7 Hz, 1H), 3.40 (s, 3H), 2.58 (dd, J = 6.6, 1.0 Hz, 6H).

[0174] 13 C NMR (76 MHz, CDC13) ô 156.75, 150.74, 132.92, 132.86, 131.93, 131.43, 130.94, 129.60, 129.12, 127.48, 127.44, 126.89, 126.19, 125.73, 125.45 (2C), 124.92, 123.37, 121.47, 114.81, 60.54, 17.35, 17.22.

[0175] Compound (I-2): To a solution of chiral substituted alcohol (II-2) (1.64 g, 4.98 mmols) in anhydrous THF (50 ml) was added sodium hydride (219 mg, 5.48

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184] mmol) at room temperature. After stirring for 15 minutes at this temperature, this reaction mixture was added dropwise to a thiophosgene solution (1.146 mL, 14.95 mmol) in anhydrous THF (50 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 h before being concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / Pentane 1 / 99 to 5 / 95) to obtain the compound chlorothionate (I-2) (1.42 g, 70% yield) as a white solid. pf: 119-121°C Rf = 0.35 (Et2O / Pentane - 2 / 98) 1 H NMR (400 MHz, CDC13) ô 7.93 - 7.88 (m, 2H), 7.82 (t, J = 1.0 Hz, 1H), 7.79 (dt, 7=8.4, 1.0 Hz, 1H), 7.52-7.46 (m, 1H), 7.34 (ddd, J= 8.1, 6.3, 1.6 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.17 - 7.01 (m, 2H), 3.37 (s, 3H), 2.55 (dd, J= 13.6, 1.0 Hz, 6H). 13 C NMR (101 MHz, CDC13) ô 183.11, 155.78, 150.79, 132.75, 132.47, 132.22, 131.23, 130.99, 130.84, 130.23, 129.25, 127.70, 127.26, 126.62, 126.55, 126.45, 126.42, 125.76, 125.39, 124.98, 122.19, 60.58, 17.31, 17.23. HRMS (ESI) exact molar mass calculated for C24HigO2ClNaS+: m / z 429.06865 ([M + Na]+), found: m / z 429.06804 ([M + Na]+). IR(film) vmax: 3057, 2936, 1499, 1461, 1445, 1408, 1360, 1264, 1243, 1200, 1146, 1104, 1087, 1044, 1009, 985, 884, 752 cm1. Example 3: Use of chlorothionate (I-1) for the separation of a racemic mixture of alcohols Chlorothionate of formula (I-1) as prepared in Example 1 was used for the separation of a racemic complex alcohol according to Scheme 3 of synthesis below: [Chem. 12]

[0185] Compounds (IVa-1) and (IVb-1): To a solution of a racemic complex alcohol 6 (22 mg, 0.06802 mmol) in anhydrous THF (4.6 mL), lithium bis(trimethylsilyl)amide (IM in THF, 340 µl) was added dropwise at 0°C. The resulting reaction mixture was stirred at this temperature for 20 minutes. The chlorothionate compound (I-1) (52 mg, 0.13604 mmol) was then added at this temperature. The resulting mixture was stirred at 35°C for a further 30 minutes, then a mixture of NH4Cl and water (volume ratio: 1 / 1, 10 mL) was added at room temperature and the whole was diluted with EtOAc (10 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 x 3 ml). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure.The crude product obtained was purified by silica gel chromatography (eluent: EtOAc / PET - 5 / 5) to obtain the thiocarbonate compounds (IV a -1) (18.1 mg) and (IVb-1) (18.4 mg) easily separable as white solids, with respective yields of 40% and 41% (overall yield of 81%).

[0186] Compound (IV a -1)

[0187] pf = 132-134°C

[0188] Rf = 0.57 (EtOAc / PET - 5 / 5)

[0189] 1 H NMR (300 MHz, CDC13) ô 8.05 - 7.96 (m, 2H), 7.97 - 7.92 (m, 1H), 7.88 - 7.81 (m, 1H), 7.51 - 7.27 (m, 7H), 7.25 - 7.19 (m, 1H), 5.57 (t, J = 2.4 Hz, 1H), 4.26 (d, J = 10.3 Hz, 1H), 4.00 - 3.86 (m, 2H), 3.83 (d, J = 10.4 Hz, 1H), 3.72 (s, 3H), 3.41 (dd, J = 10.9, 3.8 Hz, 1H), 3.13 - 3.01 (m, 1H), 2.58 (dd, J= 11.2, 4.4 Hz, 1H), 2.47-2.19 (m, 5H), 2.10 - 1.96 (m, 2H), 1.89 - 1.78 (m, 1H), 1.67 (d, J= 10.2 Hz, 3H), 1.56 -1.05 (m, 7H), 0.91 - 0.78 (m, 2H).

[0190] 13 C NMR (75 MHz, CDCl 3 ) δ 193.74, 171.01, 155.30, 148.77, 133.88, 133.73, 132.19, 130.55, 129.44, 128.94, 128.36, 128.01, 126.91, 126.70 (2C), 126.02, 125.99, 125.53, 123.74, 121.83, 116.50, 113.38, 86.19, 80.04, 68.32, 62.71, 60.94, 56.45, 46.74, 44.40, 40.89, 35.96, 33.25, 30.96, 26.08, 24.00, 20.58, 20.26, 18.97, 14,27.

[0191] [a]25 D = +85.24 0 (c = 0.53 CHC13 )

[0192] HRMS (ESI) exact molar mass calculated for C4oH4406NS+: m / z 666.28839 ([M + H]+), found: m / z666.28827 ([M + H]+).

[0193] IR(film) vmax : 3058, 2929, 2857, 1736, 1622, 1592, 1508, 1463, 1353, 1289, 1274, 1251, 1208, 1166, 1130, 1086, 1046, 897, 811, 751 cm1.

[0194] Compound (I Vb-1)

[0195] mp =132-134°C

[0196] Rf = 0.43 (EtOAc / PET - 5 / 5)

[0197] 1 H NMR (600 MHz, CDCl 3 ) 8.01 (d, J = 8.9 Hz, 1H), 7.96 (dd, J = 8.7, 5.4 Hz, 2H), 7,80 (d, J = 8,3 Hz, 1H), 7,47 (ddd, J = 13,9, 7,6, 3,4 Hz, 3H), 7,33-7,27 (m, 3H), 7,18-7,12 (m, 2H), 5,43 (d, J = 2,5 Hz, 1H), 4,28 (d, J = 10,4 Hz, 1H), 4,05 (tq, 7= 7,2, 3,2 Hz, 2H), 3,94 (d, J = 10,4 Hz, 1H), 3,85 (m, 3H), 3,02 (td, J = 12,4, 3,7 Hz, 1H), 2,71 (dd, J = 11,2, 4,0 Hz, 1H), 2,57 (dd, J = 12,8, 4,7 Hz, 1H), 2,48-2,34 (m, 4H), 2,30-2,18 (m, 2H), 2,08 (s, 2H), 1,94 (td, J = 12,5, 2,8 Hz, 1H), 1,70 (dt, J = 18,3, 12,6 Hz, 4H), 1,54 - 1,09 (m, 5H), 0,99 - 0,81 (m, 2H).

[0198] 13 C NMR (151 MHz, CDC13) ô 193,99, 171,11, 155,19, 149,22, 133,89, 133,53, 132,22, 130,58, 129,31, 129,07, 128,37, 127,86, 126,79, 126,68, 126,44, 126,34, 126,01, 125,94, 123,85, 122,37, 117,31, 113,62, 86,22, 79,97, 67,46, 62,99, 60,98, 57,23, 46,71, 44,40, 40,97, 36,08, 33,48, 30,94, 26,09, 24,01, 20,62, 20,24, 18,97, 14,31.

[0199] [a]25D= - 12,94 ° (c = 0,85 CHC13)

[0200] HRMS (ESI) exact calculated molar mass for C40H44O6NS+: m / z 666.28839 ([M + H]+), found: m / z666.28827 ([M + H]+).

[0201] IR(film) vmax: 2928, 2856, 1735, 1622, 1593, 1509, 1464, 1353, 1289, 1264, 1251, 1214, 1167, 1130, 1086, 1046, 902, 812, 751 cm1

[0202] Example 4: Use of chlorothionate (I-2) for the separation of a racemic mixture of alcohols

[0203] Chlorothionate of formula (I-2) as prepared in Example 2 was used for the separation of racemic menthol according to the synthesis scheme 4 below:

[0204] [Chem. 13] DIAGRAM 4

[0205] Compounds (IVa-2) and (IVb-2): to a solution of (±)-menthol 6 (12.5 mg, 0.0800 mmol) in DCM (2 ml) pyridine (25.9 µl, 0.3200 mmol) and then the chlorothionate compound (I-2) (65.1 mg, 0.1600 mmol) at room temperature. The resulting mixture was stirred at this temperature for 48 h, then a saturated aqueous solution of NaHCO3 (2 mL) was added at room temperature. The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 2 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (eluent: Et2O / PET-3 / 97) to obtain the readily separable thiocarbonate compounds (I-Va-2) (20.6 mg) and (IVb-2) (20.9 mg) as white solids, with respective yields of 49% and 50% (overall yield of 99%).

[0206] Compound (I Va-2 )

[0207] pg = 56-58°C

[0208] Rf = 0.29 (Et2O / PET - 5 / 100)

[0209] 1 H NMR (300 MHz, CDC13) ô 7.92 - 7.84 (m, 2H), 7.76 - 7.69 (m, 2H), 7.44 (ddd, J = 8.2, 6.3, 1.7 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.25 - 7.08 (m, 3H), 4.64 (dt, J = 10.7, 5.4 Hz, 1H), 3.30 (d, J= 9.8 Hz, 3H), 2.56 - 2.45 (m, 6H), 1.84 - 1.46 (m, 5H), 1.38 -1.20 (m, 3H), 1.13 (d, J = 7.6 Hz, 1H), 0.98 - 0.56 (m, 9H).

[0210] 13 C NMR (101 MHz, CDC13) ô 192.34, 155.79, 132.85, 132.45, 132.20, 131.17, 131.04, 130.85, 130.32, 129.90, 129.73, 127.68, 127.46, 126.87, 126.52, 126.20, 126.01, 125.97, 125.84, 125.05, 124.82, 84.54, 60.61, 46.58, 38.37, 34.11, 31.09, 26.26, 23.37, 21.80, 20.61, 17.38, 17.34, 16.67.

[0211] [a]25 D = -57.81 ° (c = 0.8167 CHC13)

[0212] HRMS (ESI) exact mass calculated for C34H38O3NaS+: m / z 549.24339 ([M + Na] +), found: m / z 549.24253 ([M + Na]+); exact mass calculated for C34H38O3KS+: m / z 565.21732 ([M + K]+), found: ni / z 565.21659 ([M + K]+).

[0213] IR(film) vmax : 3055, 2954, 2927, 2869, 1500, 1456, 1361, 1292, 1240, 1213, 1197, 1176, 1148, 1103, 1011, 882, 751 cm1.

[0214] Composé (I Vb- 2)

[0215] p. f. =56-58°C

[0216] Rf = 0,23 (Et2O / PET - 5 / 100)

[0217] 1 H NMR (300 MHz, CDC13) ô 7,92 - 7,85 (m, 2H), 7,76 - 7,67 (m, 2H), 7,48 - 7,40 (m, 1H), 7,30 (dddd, J= 8,2, 6,8, 5,6, 1,4 Hz, 2H), 7,23 - 7,06 (m, 3H), 4,73 - 4,55 (m, 1H), 3,30 (d, J = 9,8 Hz, 3H), 2,55 - 2,46 (m, 6H), 2,00 (d, J= 12,3 Hz, 1H), 1,63 - 1,43 (m, 4H), 1,36 - 1,23 (m, 3H), 0,95 - 0,55 (m, 10H).

[0218] 13 C NMR (101 MHz, CDC13) ô 192,10, 155,64, 132,84, 132,48, 132,21, 131,05, 131,02, 130,85, 130,69, 130,31, 129,80, 127,69, 127,61, 126,92, 126,46, 126,11, 126,00, 125,97, 125,83, 124,95, 124,81, 84,52, 60,43, 46,86, 39,15, 34,16, 31,36, 26,07, 23,51, 22,04, 20,39, 17,34, 17,19, 16,39.

[0219] [a]25 D = - 115,29 ° (c = 0,8333 CHC13)

[0220] HRMS (ESI) exact mass calculated for C34H38O3NaS+: m / z 549.24339 ([M + Na]+ ), found: m / z 549.24253 ([M + Na]+); exact mass calculated for C34H38O3KS+: m / z 565.21732 ([M + K]+), found: ni / z565.21650 ([M + K]+).

[0221] IR(film) vmax: 3053, 2954, 2927, 2869, 1500, 1460, 1363, 1293, 1240, 1213, 1197, 1176, 1148, 1103, 1011, 890, 750 cm1.

[0222] Example 5: Barton-McCombie reaction from separated thiocarbonates

[0223] Each of the diastereomers (IV a -1) and (I Vb-1 ) prepared in Example 3 was engaged in the Barton-McCombie reaction to form the corresponding alkane according to the following synthetic scheme 5:

[0224] [Chem. 14] ;(Vf> ÎJ DIAGRAM 5

[0225] Compound 7 [respectively compound 8]: To a solution of compound (I Va-1) [respectively compound (I Vb-1)] (15 mg, 0.02253 mmol) in anhydrous toluene (3.3 mL), tributyltin hydride (121 µl, 0.45055 mmol) and then razobisisobutyronitrile (7.4 mg, 0.04506 mmol) were added at room temperature. The resulting reaction mixture was stirred at 105°C for 1 h before being quenched with KF (45 mg, 0.77457 mmol) at room temperature. The reaction mixture was stirred for a further 10 minutes at this temperature before being concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: EtOAc / PET - 2 / 8 to EtOAc / PET / Et3N - 8 / 2 / 0.01) to obtain compound 7 [respectively compound 8] (6.2 mg, 90% yield) in the form of a colorless oil.

[0226] Rf = 0.55 (EtOAc / PET - 8 / 2)

[0227] 1 H NMR (400 MHz, CDC13) ô 4,44 (q, J= 10,4 Hz, 2H), 4,11 (q, J = 7,1 Hz, 2H), 3,92 - 3,83 (m, 1H), 3,31 - 3,14 (m, 2H), 2,70 (d, J = 11,5 Hz, 1H), 2,54 - 2,39 (m, 3H), 2,34 (td, J= 12,0, 3,5 Hz, 1H), 1,82 - 1,68 (m, 3H), 1,67 - 1,20 (m, 12H), 1,20 -1,10 (m, 1H), 0,96 - 0,80 (m, 1H).

Claims

1. Demands Chiral chlorothionate compound, derived from a chiral binol, characterized in that it corresponds to the following formula (I) or (!'): [Chem. 15]

2.

3.

4. in which: * R1 is an alkyl group or an aryl group, * R2 is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or a carbonyl group -C(=O)-R3, in which R3 is a heteroalkyl, alkyl, or aryl group. Compound according to claim 1, characterized in that R1 is an alkyl group. Compound according to claim 1 or 2, characterized in that R2 is a hydrogen atom or an alkyl group. A compound according to any one of the preceding claims, characterized in that it is selected from the following compounds: [Chem. 16]

5. A process for preparing a chlorothionate compound (I) or (II') as defined in any one of the preceding claims, characterized in that it comprises at least one step (i) of reacting a chiral substituted alcohol, derived from a chiral binol, in the presence of thiophosgene and a strong base, said chiral substituted alcohol corresponding to the following formula (II) or (II'): [Chem. 17] in which R1 and R2 are as defined in any one of the preceding claims.

6. Use of a chiral chlorothionate compound (I) or (!') as defined in any one of claims 1 to 4, for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol.

7. A method for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol, characterized in that it comprises at least the following steps: a) coupling an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (!') as defined in any one of claims 1 to 4, to form two corresponding thiocarbonate diastereomers, and b) separating the two corresponding thiocarbonate diastereomers.

8. A process according to claim 7, characterized in that it further comprises a step c) of deprotection of at least one of the diastereomers recovered in step b) to form said alcohol, in an enantiopure form.

9. Use of a chiral chlorothionate compound (I) or (!') as defined in any one of claims 1 to 4, for the deoxygenation of an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes in corresponding enantiopure alkanes.

10. A process for deoxygenating an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds, characterized in that it comprises at least the following steps: a) coupling an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (!') as defined in any one of claims 1 to 4, to form two corresponding thiocarbonate diastereomers, b) separating the two corresponding thiocarbonate diastereomers, and d) reducing at least one of the two thiocarbonate diastereomers in the presence of a hydride donor.